Ophthalmic lubricating solution adapted for use in lasik surgery

ABSTRACT

Ocular lubricant solutions are described. The solutions are adapted to facilitate the formation of a corneal flap during LASIK surgery. The solutions contain one or more viscosity enhancing agents (e.g., chondroitin sulfate) in a substantially salt-free, ophthalmically acceptable vehicle. Methods of lubricating the cornea to facilitate flap formation are also described.

This application claims priority from International Patent ApplicationNo. PCT/US01/44533 filed on Nov. 29, 2001, which claims priority fromU.S. Provisional Application Ser. No. 60/257,304, filed on Dec. 20,2000.

BACKGROUND OF THE INVENTION

The present invention is directed to the field of ophthalmic surgery.More specifically, the invention is directed to a lubricating solutionthat may be utilized during various ophthalmic procedures, but isparticularly useful in facilitating the formation of a corneal flapduring laser in situ keratomileusis (“LASIK”).

LASIK surgery involves the use of a microkeratome to make an incision inthe cornea transverse to the optical axis. This incision results in theformation of a corneal flap which is temporarily lifted and folded backso as to expose underlying tissue which is then sculpted or ablated witha laser so as to modify the curvature of the cornea and thereby correctthe vision of the patient. For further background regarding LASIKsurgery, particularly the formation of the corneal flap by means of amicrokeratome, please refer to the following publications:

Pallikaris et al., “Laser In-Situ Keratomileusis”, Lasers in Surgery andMedicine, volume 10, Pages 463-468 (1990);

Carr et al., “Laser In-Situ Keratomileusis”, Ophthalmology Clinics ofNorth America volume 10, pages 533-543 (1997);

Gimbel et al., “Indications, Results, and Complications of LASIK”,Current Opinion in Ophthalmology, volume 9, pages 3-8 (1998);

Farah et al., “Laser In-Situ Keratomileusis: Literature Review of aDeveloping Technique” Journal of Cataract and Refractive Surgery, volume24, pages 1059-1063 (1998); and

Wilson, “LASIK Surgery”, AORN Journal, volume 71, pages 963-983 (2000).

Although the LASIK surgical procedure has now been conducted onthousands of patients, certain aspects of the procedure occasionallygive rise to complications. The formation of the corneal flap is oneaspect of the overall LASIK procedure which can give rise tocomplications. Specifically, the formation of the corneal flap canresult in epithelial abrasions or other damage due to the microkeratomeblade, and the cut or incision by means of the microkeratome blade cansometimes be somewhat unpredictable. Moreover, in some patients, cornealhaze or edema subsequent to surgery and flap wrinkles or curled flapedges have been attributed to problems in forming the corneal flap withthe microkeratome. The failure of the flap to reseal following surgeryis also a significant complication, because such failure creates agreater risk of infection and may adversely affect visual acuity.

In view of the foregoing, there is a need for products which willenhance the ability of surgeons to form the corneal flap withoutdamaging the cornea or associated ophthalmic tissues. In particular,there is a need for products which: (1) help to minimize cornealepithelial abrasions; (2) facilitate smooth, consistent cuts; and (3)expedite post-operative visual acuity by facilitating formation of aflap that is not wrinkled, fits well upon replacement and seals readilyfollowing the LASIK procedure.

Various types of solutions are currently being applied to the corneaprior to use of the microkeratome to form the corneal flap in LASIKsurgical procedures. However, none of these solutions has been designedto meet the needs of the ophthalmic surgeon in conjunction with LASIKsurgery. Consequently, each of these solutions has one or moredrawbacks. For example, some of the solutions provide at least minimallubrication, but contain other ingredients (e.g., antimicrobialpreservatives) which are potentially toxic to the cornea and thereforehighly undesirable in conjunction with an invasive surgical proceduresuch as LASIK surgery. Thus, the solutions currently being utilized are,at best, less than ideal.

The prior solutions have also created a problem with respect to thesurgical devices utilized in the LASIK procedure. Specifically, thebalanced salt solutions and other electrolyte-containing solutions whichhave been used to lubricate the cornea prior to formation of the cornealflap with a microkeratome contain relatively high concentrations ofsodium chloride and other salts. The microkeratome is a very delicate,precise surgical instrument that includes a small motor and agear-driven blade. The effectiveness and accuracy of the microkeratomein forming the corneal flap is directly dependent on the motor andgears. It has been found that the electrolyte solutions can create acorrosion or gumming problem on the motor and/or gears of themicrokeratome and thereby interfere with its performance. Thus, there isa need not only for a lubricant solution which enhances the ability ofthe surgeon to form the corneal flap, but also for a solution which doesnot have any negative effects on the performance of the microkeratome.

SUMMARY OF THE INVENTION

The present invention provides an improved lubricating solution fortopical application to the cornea in conjunction with ophthalmicsurgical procedures, particularly the formation of a corneal flap inconjunction with LASIK surgery.

The lubricating solution of the present invention is salt-free, andtherefore does not create a risk of corrosion to the motor, gear systemor other components of microkeratome devices.

The solutions of the present invention are also unpreserved, that is,the solutions do not contain antimicrobial preservatives (e.g.,benzalkonium chloride). Such preservatives are potentially harmful tothe cornea, particularly in patients undergoing LASIK surgery.

Finally, the solutions of the present invention contain aviscosity-enhancing agent to modify the lubricity or tackiness of thesolution upon application to the cornea. The viscosity-enhancing agentfacilitates formation of the corneal flap with less force and lesspotential damage to the tissues from either the microkeratome blade orthe vacuum ring is utilized to hold the cornea in place during formationof the corneal flap.

DETAILED DESCRIPTION OF THE INVENTION

The lubricant solutions of the present invention are substantiallysalt-free. As utilized herein, the phrase “substantially salt-free”means that the solutions contain only incidental amounts of ionic saltssuch as sodium chloride or, preferably, do not contain any ionic salts.

Because ionic salts are largely absent from the solutions of the presentinvention, it is necessary to adjust the osmolality of the solutionswith other types of materials. Various non-ionic osmolality-adjustingagents can be utilized for this purpose. Examples of such agents includevarious polyhydric alcohols, such as glycerol, mannitol, sorbitol,propylene glycol, and so on. The most preferred non-ionic osmolalityadjusting agent is glycerol.

The above-described non-ionic osmolality adjusting agents will beutilized in an amount sufficient to render the solutions eitherisotonic, mildly hypotonic, or mildly hypertonic. The osmolality rangefor the solutions of the present invention will typically be about 200to 400 milliosmoles per kilogram water (“mOsm/kg”).

The lubricant solutions of the present invention are sterile and do notcontain antimicrobial preservatives such as benzalkonium chloride. Thesolutions are therefore referred to herein as being “unpreserved”.

In order to provide lubrication of the microkeratome, reduce cornealepithelial abrasions from the microkeratome blade, and produce smoothand consistent cuts with the microkeratome blade, the lubricantsolutions of the present invention include a small amount of one or moreviscosity-enhancing agents.

The viscosity-enhancing agent is preferably a polymeric material.Various pharmaceutically acceptable polymeric materials can be used forthis purpose. The preferred polymeric materials include: chondroitinsulfate, sodium hyaluronate or other proteoglycans; cellulosederivatives, such as hydroxypropyl methylcellulose (“HPMC”), carboxymethylcellulose (“CMC”), and hydroxyethyl cellulose (“HEC”); collagenand modified collagens; galactomannans, such as guar gum, locust beangum and tara gum, as well as polysaccharides derived from the foregoingnatural gums and similar natural or synthetic gums containing mannoseand/or galactose moieties as the main structural components (e.g.,hydroxypropyl guar); xanthan gum; gellan gums; alginate; chitosans;polyvinyl alcohol; carboxyvinyl polymers (e.g., carbomers such as theCarbopol™ brand polymers available from B. F. Goodrich); and variousother viscous or viscoelastomeric substances, including but not limitedto those described in U.S. Pat. No. 5,409,904 (Hecht, et al.), theentire contents of which are hereby incorporated by reference in thepresent specification.

The following patent publications may be referred to for further detailsconcerning the above-listed viscosity-enhancing agents: U.S. Pat. No.4,861,760 (gellan gums); U.S. Pat. No. 4,255,415 and WIPO PublicationNo. WO 94/10976 (polyvinyl alcohol); U.S. Pat. No. 4,271,143(carboxyvinyl polymers); WIPO Publication No. WO 99/51273 (xanthan gum);and WIPO Publication No. WO 99/06023 (galactomannans). The entirecontents of the foregoing references pertaining to the structures,chemical properties and physical properties of the respective viscosityenhancing agents described above are hereby incorporated in the presentspecification by reference.

The most preferred viscosity-enhancing agent is chondroitin sulfate. Theuse of chondroitin sulfate in an amount of 0.1 to 10 w/v % allows theabove-stated objectives to be achieved. Moreover, the use of chondroitinsulfate is also advantageous in that it can serve not only as theviscosity-enhancing agent, but also as an osmolality-enhancing agent.

As indicated above, the viscosity-enhancing agent modifies the lubricityor tackiness of the lubricant solution so as to facilitate the formationof the corneal flap with less force applied to the microkeratome blade.The viscosity-enhancing agent also helps to prevent damage to ophthalmictissue from the microkeratome blade or the vacuum ring that is appliedto the cornea to hold it in place. The amount of polymeric materialrequired in order to achieve these objectives is referred to herein as“an effective amount”. The amount required will vary depending on thepolymeric material or combination of materials selected in a given caseand other considerations. However, the concentration of the polymericmaterial in the lubricant solutions of the present invention willgenerally be in the range of from about 0.1 to about 10 weight/volumepercent (“w/v %”), and the viscosity of the solutions will generally bein the range of 1 to 50 centipoises (“cps”), preferably 3 to 30 cps.

The lubricant solutions of the present invention may be utilized inconjunction with various types of ophthalmic surgical procedures, butare particularly adapted for use in LASIK surgery. The solutions may beutilized to facilitate formation of the corneal flap by applying a fewdrops of the solution to the cornea immediately before the microkeratomeis applied to the cornea.

Although the solutions of the present invention are primarily intendedto be utilized during LASIK surgery to facilitate formation of thecorneal flap, the lubricant properties of the solutions also makes thesolutions quite useful for post-surgical application by the physician orpatient. Patients who have LASIK surgery frequently report feelings ofdryness, increased sensitivity or other minor irritations subsequent tothe surgical procedure. The solutions of the present invention may beemployed to alleviate or reduce these types of post-surgical symptoms.

The following examples are provided to further illustrate the lubricantsolutions of the present invention.

EXAMPLE 1

Amount Ingredient (w/v %) Chondroitin Sulfate 0-10 Glycerin 1-3% (toadjust tonicity) Hydrochloric acid/Sodium Hydroxide qs to pH 6.5-8.5Water for Injection qs to volumeThe solution is prepared by dissolving appropriate amount of glycerin inwater for injection at about 20° C. to adjust the osmolality of thesolution to the desired level. Chondroitin sulfate is then added to thesolution to make the concentration of chondroitin sulfate in the rangeof 0 to 10% weight by volume. The pH of the solution is adjusted to therange of 6.5 to 8.5 by adding 1N HCl or 1N NaOH. Additional water forinjection is then added to bring the solution to its final volume.

EXAMPLE 2

Amount Ingredient (w/v %) Hydroxypropyl Methylcellulose (HPMC) 0-1 Glycerin 1-3% Hydrochloric acid/Sodium Hydroxide qs to pH 6.5-8.5 Waterfor Injection qs to volumeThe solution is prepared by dissolving appropriate amount of glycerin inwater for injection at about 20° C. to adjust the osmolality of thesolution to the desired level. The solution is heated till it is aboutto boil. Hydroxypropyl methylcellulose is then added to the heatedsolution under rigorous stirring to make the concentration of HPMC inthe range of 0 to 1% weight by volume. The solution is removed from heatand let cool to room temperature under continuous stirring. The solutionis then stored under refrigeration overnight to facilitate completehydration of HPMC. The next day the solution is brought to roomtemperature and the pH of the solution is adjusted to the range of 6.5to 8.5 by adding 1N HCl or 1N NaOH. Additional water for injection isthen added to bring the solution to its final volume.

1. A method of facilitating the formation of a corneal flap in LASIKsurgery by means of a microkeratome and reducing the risk of abrasionsto corneal tissue during the formation of said flap, which comprisesapplying an ocular lubricant solution to the corneal surface of an eyeimmediately before the microkeratome is applied to the eye, saidsolution comprising a viscosity-enhancing agent in an amount effectiveto enhance the viscosity of the solution, and an ophthalmicallyacceptable vehicle for said viscosity-enhancing agent, wherein thesolution is sterile, unpreserved and substantially salt free.
 2. Amethod according to claim 1, wherein the lubricant solution has aviscosity of 1 to 50 cps.
 3. A method according to claim 1, wherein theviscosity-enhancing agent is selected from the group consisting of:proteoglycans; cellulose derivatives; collagen or modified collagen;galactomannans; xanthan gum; gellan gum; alginate; chitosans; polyvinylalcohol; and carboxyvinyl polymers.
 4. A method according to claim 3,wherein the viscosity-enhancing agent comprises a proteoglycan.
 5. Amethod according to claim 4, wherein the proteoglycan is selected fromthe group consisting of chondroitin sulfate and sodium hyaluronate.
 6. Amethod according to claim 5, wherein the viscosity-enhancing agentcomprises chondroitin sulfate.
 7. A method according to claim 1, whereinthe lubricant solution has a viscosity of 3 to 30 cps.